A Review of Systemic Lupus Erythematosus (SLE): Symptoms, Risk Factors, Treatment, and Health Related Quality of Life Issues

In this paper, we present a thorough review of one of the most life-threatening autoimmune diseases, Systemic lupus erythematosus (lupus). Symptoms, risk factors, including genetic and epidemiological factors are discussed. Treatment, life expectancies, and Health Related Quality of Life of patients with SLE will be discussed as well. Special attention will be given to Lupus Nephritis.


Introduction
Autoimmune system disorders cause abnormally low activity or overactivity of the immune system. In cases of immune system overactivity, the body attacks and damages its own tissues (autoimmune diseases). Immune deficiency diseases decrease the body's ability to fight invaders, causing vulnerability to infections. In response to an unknown trigger, the immune system may begin producing antibodies that instead of fighting infections, and attack the body's own tissues. When the immune system determines that healthy cells are foreign, it begins to produce antibodies to fight off the healthy cells. It is believed to be the source of an illness or infection. When an autoimmune disease is suspected, a rheumatologist will administer tests to determine what antibodies are being produced. Treatment for autoimmune diseases generally focuses on reducing immune sys-

Risk Factors for SLE
Scientists divide risk factors associated with SLE into three groups; environmental, we divide the risk factors for Lupus into two groups; the first is related to environmental and the other is genetic factors.

Environmental Risk Factors
Aggregate data from population base studies reported that approximately 90% of patients with SLE are female, and the incidence of SLE among African Americans is increased 3 -4-fold compared with that among Caucasians [19] [20]. It is therefore postulated that gender is a non-modifiable risk factor of prime importance.
There is strong epidemiologic evidence linking environmental factors, including current cigarette smoking, vitamin D level infections such as Epstein-Barr virus, dietary factors. In the following section we list some of these environmental risk factors.

Cigarette Smoking
Mechanistic evidence exists implicating smoking in SLE pathogenesis. Exposure to toxic components from cigarette smoke (e.g. tars, nicotine, carbon monoxide, polycyclic aromatic hydrocarbons and free radicals) can induce oxidative stress and directly damage endogenous proteins and DNA, leading to genetic mutations and gene activation, which could be involved in development of SLE [19]. Cigarette smoking stimulates the expression of CD95 on B and CD4 T cell surfaces, potentially inducing autoimmunity [20], and augments production of pro-inflammatory cytokines [21]. In a retrospective case-control study of SLE patients, current smokers were significantly more likely to have anti-double stranded DNA antibodies compared to never smokers [21]. Additionally, smoking leads to the formation of immunogenic DNA adducts with a half-life of 9 to 13 weeks, which may explain why current smoking has been more strongly associated with increased SLE risk [21]. However, two additional case-control studies performed since then have demonstrated an elevated risk for both current and former smokers compared to never smokers [22] [23].
Vitamin D Further complicating our understanding of the relationship between UV radiation and SLE pathogenesis is the controversial role of Vitamin D. While exposure to solar UV radiation may trigger SLE disease flares, UV light exposure is also the main source of vitamin D production [24]. Vitamin D may be immunosuppressive once metabolized to 1α, 25(OH) 2 D, and it has been suggested that UV-B radiation could reduce SLE risk via stimulation of cutaneous vitamin D synthesis [25]. Many cross-sectional and case-control studies have reported low 25(OH) vitamin D concentrations in SLE patients compared to controls, however, it is not clear whether low vitamin D is a cause or consequence of chronic disease.
Infections (EBV) seropositivity rates are much higher in adults and children with SLE Open Journal of Rheumatology and Autoimmune Diseases than age-matched controls [26]. Potential mechanisms involve Epstein-Barr virus protein complexes inducing type 1 interferon via Toll-like receptor 3 and molecular mimicry between EBV and SLE antigens [27]. Additionally, SLE patients have impaired CD8+ cytotoxic T cells, and irregular cytokine production in plasmacytoid dendritic cells and CD69+ CD4+ T cells in response to EBV.
However, no conclusive data have established that EBV infection is linked to future risk of SLE. Notably, in a large population-based Danish cohort, EBV-serologic negative individuals had a sustained increased risk for SLE highest in the 1 to 4 years after testing (standardized incidence rate, 6.6; 95% CI, 3.3 -13.2), but this finding may have been due to a surveillance bias as EBV testing is likely to be performed during the work-up for early SLE symptoms [28]. In that study, no associations were found with EBV serologic positivity, infectious mononucleosis, or severe infectious mononucleosis requiring hospitalization [28] [29]. Therefore, the association between EBV and incident SLE, in particular the question of causality, remains to be fully elucidated.

Air Pollution
Particulate air pollution has effects like those of inhaled cigarette smoke and silica on the immune system and has been linked to asthma, chronic bronchitis, cardiovascular disease, and lung and laryngeal cancers [30] [31].
Heavy Metals Data from experimental studies suggest that heavy metals may increase systemic autoimmunity, and that co-exposure to certain heavy metals may increase the risk associated with other exposures [32]. Mercury-exposed gold miners were demonstrated to have a higher prevalence of detectable ANA as compared to diamond and emerald miners with no occupational mercury exposure [33].
Dietary Factors and Medications While there are very few prospective studies of dietary intake and SLE, several lines of evidence implicate dietary factors in SLE pathogenesis. First, murine models suggest that dietary exposures can induce epigenetic changes and SLE autoimmunity [34] [35]. When genetically-SLE predisposed C57BL/6 × SJL mice were fed methyl donor poor diets, they developed lupus nephritis, whereas those fed diets rich in methyl group micronutrients did not [36] [37] [38]. As oxidative stress, inflammation and cytokine dysregulation are central to SLE pathogenesis, diet may play an important accelerating role. Prior studies suggest that high intake of certain antioxidants; fish, olive oil and cooked vegetables may confer a protective effect against chronic disease development [38]. Women consuming > 200 mL of coffee per day had increased inflammation markers, such as interleukin-6 and tumor necrosis factor-α, compared with coffee non-drinkers [38]. A prior case-control study suggests a significant increased SLE risk with black tea consumption and borderline increased risk with coffee consumption, but not green tea [38].

Genetic Risk Factors
During the past few years extensive research on the genetic bases of SLE has S. N. Al-Gahtani Open Journal of Rheumatology and Autoimmune Diseases emerged. Genetic variation was first shown to be important in SLE in the 1970s with associations in the human leukocyte antigen region. Almost four decades later, and with the help of increasingly powerful genetic approaches, more than 25 genes are now known to contribute to the mechanisms that predispose individuals to lupus [39]. Over half of these loci have been discovered in the past 2 years, underscoring the extraordinary success of genome-wide association approaches in SLE. Well-established risk factors include alleles in the major histocompatibility complex region (multiple genes), IRF5, ITGAM, STAT4, BLK, BANK1, PDCD1, PTPN22, TNFSF4, TNFAIP3, SPP1, some of the Fcg receptors, and deficiencies in several complement components, including C1q, C4 and C2.
As reviewed here, many susceptibility genes fall into key pathways that are consistent with previous studies implicating immune complexes, host immune signal transduction and interferon pathways in the pathogenesis of SLE. Other loci have no known function or apparent immunological role and have the potential to reveal novel disease mechanisms. Certainly, as our understanding of the genetic etiology of SLE continues to mature, important new opportunities will emerge for developing more effective diagnostic and clinical management tools for this complex autoimmune disease.
In the past 2 years, a series of landmark studies have been reported that have revolutionized our understanding of the genetics of lupus. These are composed of insightful candidate gene studies and are anchored by genome-wide association (GWA) studies that include more than 10,000 individuals of European descent genotyped at over 300,000 single nucleotide polymorphisms (SNPs). Successful mapping of risk loci for lupus is comparable to inflammatory bowel disease where over 30 loci have now been identified [40]. SLE has long been considered a prototypic autoimmune disease, and from the genetics perspective, has served that title well. The coming years will most certainly continue to reveal additional associations, refinements to our current understanding of those established thus far and provide new clues to explain the clinical heterogeneity that is a hallmark of SLE. Additional work will include detailed genetic studies in multiple ethnic groups, the development of models of disease that incorporate environmental influences, and studies to determine the overlapping and unique relationships among genetic variants associated with other related autoimmune phenotypes. Every robust, authentic association has a compulsory role in pathogenesis, which promises to change profoundly our capacity to diagnose, predict and treat human disease [40] [41].
A recent paper [42] focusing on the Genome-wide association studies of Systemic Lupus Erythematosus (SLE) nominated 3073 genetic variants at 91 risk loci. To systematically screen these variants for allelic transcriptional enhancer activity, the authors construct a massively parallel reporter assay (MPRA) library comprising 12,396 DNA oligonucleotides containing the genomic context around every allele of each SLE variant. Collectively, their approach provided a blueprint for the discovery of allelic gene regulation at risk loci for any disease and offers Open Journal of Rheumatology and Autoimmune Diseases insight into the transcriptional regulatory mechanisms underlying SLE.

Genetic Epidemiology of SLE: Studies on the Familial Aggregation of SLE
Family studies are the only design that helps quantifying the inheritance of SLE and its clustering among family members. Only a few studies have looked at familial aggregation of SLE on a nationwide level. In a recent cohort study from Taiwan, 18 283 [43] persons were identified as having SLE. Among these, 607 first-degree relatives had SLE, corresponding to an overall 17 times increased risk of SLE in first-degree relatives and a 315 times increased risk in twins [43] [44]. The cohort was based on national health insurance data, where the insured person had to claim relatives as dependents. Hence, 20% of the cohort members were registered alone without any identifiable relative. However, the diagnosis of SLE could only be agreed upon by an expert panel from the Taiwan National.
The study [43] which is a nation-wide registry-based assessed the impact of having a family history of SLE on the risk of developing autoimmune-diseases (AD) in a population-based Danish cohort. The important findings were that the risk of developing any AD was significantly 51% and 28% elevated in individuals with a first-degree or second-or third-degree relative with SLE, respectively. The risk was substantially elevated for SLE, but also for RA, IBD, type 1 diabetes mellitus and the combined group of other ADs in individuals with an SLE-affected first degree relative. Individuals who had a co-twin or more than one first-degree relative with SLE were at a 76-and 61-times increased risk of developing SLE, respectively. There was no clear influence of the sex of the SLE-affected family member on the risk of SLE, although male cohort members with an SLE-affected male relative were at a 10-fold elevated relative risk of developing SLE as compared with the 8-fold increased risk in female cohort members. In one previous cohort study, there was a trend that men with SLE-affected male relatives were at a higher risk of SLE [44]. In summary, the study showed that a family history of

Lupus Nephritis
Lupus nephritis (LN) occurs in ~50% of patients with SLE and is the most common, but not the only, cause of kidney injury in SLE. Men with SLE tend to have more aggressive disease with higher rates of renal and cardiovascular involvement and are more likely to develop kidney failure than women [45].  [50]. Familial aggregation of SLE has also been clearly documented, and most pedigrees support a non-Mendelian complex inheritance [51]. These facts strongly support notion of a polygenic genetic contribution to SLE pathogenesis. Among the various organ manifestations of SLE, lupus nephritis (LN) is one of the most feared, potentially resulting in organ damage and renal insufficiency those results in poor clinical outcomes despite recent improvements in SLE treatment.
Genome-Wide-Association Studies (GWAS) and candidate gene association studies have revealed numerous risk genes for SLE, including loci which contain genes that function in the innate and adaptive immune system [52] [53]. Some of these genes are also closely associated with LN. However, most of these previous studies were not primarily focused on the nephritis phenotype, and less is known about which genes predispose to LN. Some recent studies which have focused on identifying the genes specifically responsible for LN have identified intrarenal genes that are associated with LN, but not associated with the susceptibility of SLE in general [54] [55]. While the exact functional mechanisms of these renal-related candidate genes remain unclear, it seems that the genetic basis of LN involves a combination of general SLE susceptibility genes which function in the immune system and genes which are more renal-specific that predispose specifically to LN.

Difference in Incidence Rate and Severity of LN between Ethnicities
Among various organ manifestations of SLE, LN is one of the most severe, and can progress to end-stage renal disease (ESRD) leading to increased morbidity and mortality. LN affects about 40% of SLE patients throughout their lifetime [56].  [56]. This disparity between ancestral backgrounds could be related to genetic or environmental factors [62]. To investigate the importance of genetic factors, Sanchez et al. conducted a study evaluating the genetic impact of the proportion of Amerindian vs. European genetic ancestry in admixed populations living in South America. This is an informative way to study the contribution of genetics to LN with some control over environment, as different individuals living in the same population and same location will have different proportional genetic ancestry. This study revealed that an increased proportion of Amerindian genetic ancestry correlated with increased risk of developing LN [47]. Another study demonstrated familial clustering of ESRD African ancestry SLE patients with LN, suggesting shared genetic factors contributing to LN in these families [63]. These studies support the idea that genetic factors contribute to the pathogenesis of LN. Not only genetic changes, but epigenetic changes (i.e., post-translational modifications) also play an important role in the pathogenesis of SLE. DNA methylation is one of the important post-translational regulatory modifications, typically occurring at CG dinucleotides. DNA methylation results in gene silencing by tightening the chromatin structure and limiting the access of transcriptional factors, while DNA hypomethylation induce transcription of genes.
Impaired DNA methylation status in CD4+ T cells of SLE patients was reported more than 20 years ago [64] [65] [66]. As next-generation sequencing technology has advanced, genome-wide methylation studies have demonstrated the differences in methylation profiles of CD4 T cells in SLE patients compared to those of healthy controls. Some studies have shown a difference in methylation profiles between different groups of SLE patients [67] [68]. Of note, hypomethylation of type I IFN-regulated genes known to play important roles in the pathogenesis of SLE are reported in SLE patients [69] [70]. More recently, Coit et al. [70] identified that there are more robust differences in methylation status of type I IFN-regulated genes when compared between SLE patients with LN and SLE patients without LN [71].
These studies shed light to another aspect of genetic involvement in the pathogenesis of SLE and LN, although there is still much work to be done to clarify their specific role to LN and take advantage of this knowledge to design treatments.

Trend in Mortality of Patients with Lupus Nephritis
A recent study on the survival rate of patients with renal diseases reported very important findings from a community-based study [72]. The rates of renal survival (i.e., survival without dialysis) in patients with lupus nephritis in the 1990s ranged from 83% to 92% over 5 years of follow up and from 74% to 84% over 10 years of follow up [73] [74] [75]. The risk of end-stage renal disease (ESRD) has Open Journal of Rheumatology and Autoimmune Diseases been particularly high in patients with diffuse proliferative glomerulonephritis, with risk estimates ranging from 11% to 33% over 5 years of follow up [76] [77] [78]. The prognosis of lupus nephritis depends on many demographics, racial, genetic, histopathologic, immunologic, and time-dependent factors [79]. Renal disease that fails to remit with immunosuppressive therapies is a major risk factor for subsequent deterioration of renal function and poor outcome [80] [81]. Recent studies have reiterated that lupus nephritis patients of African, Hispanic, or Asian ethnicity have generally experienced poorer outcomes [82] [83] [84] [85].
More recent studies have focused on the relative mortality of patients with lupus renal disease as compared to different reference groups [86]- [91]. However, the effect of different histologic classes of lupus glomerulonephritis on the relative mortality of SLE, as compared to mortality rates in the general population, has been largely unreported. Moreover, data on the life expectancy of patients with lupus nephritis are not available in the literature. Therefore, the present study was carried out to evaluate the effect of renal disease, histologic class of lupus nephritis, renal damage, and renal failure on the standardized mortality ratio (SMR) and life expectancy in a longitudinal cohort of SLE patients from China. The findings of the above research concluded that patients with SLE have increased mortality. This is due to multiple factors that include an increased susceptibility to infection, accelerated atherosclerosis, and malignancies, as well as organ damage due to treatment failure or complications [92]. The survival of patients with SLE has improved tremendously in the past 3 -4 decades, which is attributed to earlier diagnosis and treatment, more judicious use of corticosteroids, the emergence of novel treatments, and better supportive care for organ failure and infection-related complications [92]. However, the improvement in the SLE survival rate appears to have reached a plateau since the 1990s [93]. Patients with SLE still have a mortality rate higher than that of the general population [87] [91], although a dropping trend has been observed [94]. Renal disease is a major organ manifestation of SLE, and its presence further increases the risk of death, because the disease still progresses to ESRD in a constant proportion of patients over time [86]- [91].

Treatment of the Diseases
The significant diversity of lupus nephritis (LN) has been the subject of intense investigation for a long time [95]. Several attempts were made to classify the pathologic features of LN. This classification represented distinctive characteristics and hence differences in response to treatment.
Intravenous cyclophosphamide (IVCY) has been widely used as a form of therapy to induce remission of diffuse proliferative LN (also known as class IV LN) for more than 20 years [96]. Since 1997, mycophenolate mofetil (MMF) has also been used successfully for the treatment of class IV LN [97] [98] [99].
A combined therapy consisting of steroids, MMF, and tacrolimus has been applied in the field of organ transplantation for years. It was shown to be an ef- An extensive clinical trial [95] documented important findings regarding the treatment of LN and its classes. It was noted that the overlap of class V with III (Vc) and IV (Vd) was described as a subcategory of membranous LN in the 1982 World Health Organization classification but was eliminated in the 2003 ISN/RPS classification [105].
Although the cause of systemic lupus erythematosus remains elusive, the undeniable fact is that different types of LN may involve different immune pathogeneses. LN is characterized by the deposition of IgG4 and the absence of delayed type hypersensitivity effectors [106].
In summary, the therapeutic goal for patients with LN is to achieve prompt remission and avoid disease flare and chronic renal impairment. As studies have shown [107] [108] relapses of LN may be common after the induction treatment. A prolonged follow-up period is needed for the exploration of this treatment's impact on long-term prognosis and the recurrence rate during the maintenance therapy period [96].
Even with treatment, loss of kidney function sometimes progresses. If both kidneys fail, people with lupus nephritis may need dialysis. Dialysis involves filtering the blood through a machine to remove waste products from the body.
Ultimately, it may be necessary to have a kidney transplant. In those cases, people will need additional drugs to keep their immune system from rejecting the transplanted kidney.
Why is Health-Related Quality of Life & Well-Being Important? Healthy People 2020 emphasizes the importance of health-related quality of life and well-being by including it as one of the initiative's 4 overarching goals, "promoting quality of life, healthy development, and health behaviors across all life stages [109] [110]. It also was established as one of the HP2020 4 foundation health measures [111].
The significance of quality of life and well-being as a public health concern is not new. Since 1949, the World Health Organization (WHO) has noted that health is "a state of complete physical, mental, and social well-being and not merely an absence of disease and infirmity." [112]. In 2005, WHO recognized the importance of evaluating and improving people's quality of life in a position paper [113]. Because people are living longer than ever before, researchers have changed the way they examine health, looking beyond causes of death and morbidity to examine the relationship of health to the quality of an individual life.
When quality of life is considered in the context of health and disease, it's commonly referred to as health-related quality of life (HRQOL). Researchers today agree that HRQOL is multidimensional and includes domains that are re-lated to physical, mental, emotional, and social functioning and the social context in which people live [114].
HRQOL is a subjective and multidimensional concept that includes aspects of physical, mental, and social health [115] [116]. For Healthy People 2020, the Patient-Reported Outcomes Measurement Information System (PROMIS) Global Health Items were identified as reliable and valid measures of self-reported physical and mental health and are currently being considered to monitor these 2 domains across the decade. PROMIS is an NIH Roadmap initiative designed to develop an electronic system to collect self-reported HRQOL data from diverse populations of individuals with a variety of chronic diseases and demographic characteristics [117] [118].
An important study [119] on HRQOL used cross sectional data obtained from patients with systemic lupus erythematosus (SLE) during psychometric evaluation studies of Lupus from various countries were compared between those: 1) with and without LN and 2) with active and inactive-LN. Data compared included demographics, disease characteristics, and Lupus PRO constructs. Presence of LN was present if listed among the ACR classification criteria (ACR-LN), while presence of active LN was based on presence of urinary casts, hematuria, proteinuria or pyuria in the disease activity assessment (SELENA-SLEDAI) performed at the time of the study visit. Lupus PRO has Health related QOL (HRQOL) and non-HRQOL constructs. HRQOL domains include lupus symptoms, cognition, medication, procreation, physical health, emotional health, pain-vitality, and body image. Non-HRQOL domains include desires-goals, social support, coping and satisfaction with care. Non-parametric tests were used to make comparisons, and p values ≤ 0.05 were considered significant.
The results of the study are summarized here. There were 1259 SLE patients. Five-hundred and thirty-nine had ACR-LN. These patients were younger, had greater disease activity (PGA, Total SELENA-SLEDAI) and damage (SLICC/ACR) than those without LN. Summary HRQOL and non-HRQOL scores were similar in both groups; however, those with ACR-LN had significantly worse scores on medications and procreation domains, while those without ACR-LN had worse scores on Pain-Vitality domains.
129/540 ACR-LN patients had active LN. Patients with active LN were younger, had significantly greater disease activity (PGA, Total SELENA-SLEDAI), worse HRQOL and non-HRQOL than patients with inactive LN. Specific domains scores adversely affected among active LN patients were lupus symptoms, medications, procreation, emotional health, body image and desires-goals. Satisfaction with care was significantly higher among patients with active LN as compared to inactive LN patients. We conducted meta-analytic approach using components of the study (study factors) [119]. In Figure 1: study = components of the HRQOL, Experimental = LN_NO, and Control = LN_YES.
In Figure 2, study = components of the HRQOL, Experimental = ACR_LN (NO), control = ACR_LN (YES). These notations are the default naming of groups provided by the software program R.   Several important components of the HRQOL instruments need explanation in the above figures; they are "The Physician Global Assessment" (PGA). The PGA [120] is a visual analogue score that reflects the clinician's judgment of overall SLE disease activity.
Construct validity was demonstrated by a good correlation (r ≥ 0.50) between the PGA with the SLEDAI [121]. The SLEDAI is a global index that was developed and introduced in 1985 as a clinical index for the assessment of lupus disease activity in the preceding 10 days. It consists of 24 weighted clinical and laboratory variables of nine organ systems. This instrument was derived by consensus among experts in rheumatology followed by application of regression models to assign relative weights to each parameter. SLEDAI was modeled based on clinician global judgment.
A modified version of the SLEDAI (SELENA-SLEDAI) was devised for use in the Safety of Estrogens in Lupus National Assessment (SELENA) study. A glossary was added, and the scoring was modified to account for persistent active disease in some descriptors (rash, mucosal ulcers, and alopecia), which were pre-Open Journal of Rheumatology and Autoimmune Diseases viously not scored unless they were new or recurrent.
In the SELENA-SLEDAI, researchers accepted the presence of either objective or subjective findings to score the descriptor as present [19]. The SELENASLEDAI version awaits rigorous validation with other measures related to disease activity in SLE.SLEDAI-2000 SLEDAI-2000 (SLEDAI-2 K) was introduced in 2002 as a measure of global disease activity. SLEDAI-2 K is a modification of the original SLEDAI to allow the documentation of persistent.

Discussion
The fundamental goals of treatment of patients with SLE are to improve long-term patient outcomes. Management should aim at remission of disease symptoms and signs, prevention of damage accrual and minimization of drug side-effects, as well as improvement of quality of life [122] [123]. Complete remission (absence of clinical activity with no use of GC and IS drugs) is infrequent [124] [125] [126] [127] [128]. To this end, newly defined low disease activity states (based on a SLEDAI score ≤ 3 on antimalarials, or alternatively SLEDAI ≤ 4, PGA ≤ 1 with GC ≤ 7.5 mg of prednisone and well-tolerated IS agents) have shown comparable rates with remission, regarding halting of damage accrual [129] [130] [131] [132]. Accordingly, treatment in SLE should aim at remission or, if this state cannot be achieved, at low disease activity in all organ systems.
Prevention of disease flares is an additional milestone of SLE treatment. Although a universally accepted definition is lacking, most experts agree that a flare is a measurable increase in disease activity usually leading to change of treatment [133] [134] [135].
Another issue related to the human burden of the disease is "Risk of infection" associated with both disease-related and treatment-related factors; high-dose GC therapy, CYC, MMF and RTX are all associated with an increased risk for infection, while high disease activity, severe leucopenia and presence of renal involvement in nephrotic syndrome also contribute independently. Protection against infections should be proactive, focusing both on primary prevention, as well as timely recognition and treatment. Patients with lupus should receive vaccinations according to the EULAR [136] recommendations for vaccination of patients with autoimmune rheumatic diseases [137] [138]. Immunization against seasonal influenza and pneumococcal infection (both PCV13 and PPSV23) should be strongly considered, preferably during stable disease. SLE is an independent risk factor for cardiovascular disease (CVD), due to both traditional and disease-related risk factors, such as persistent disease activity, LN, presence of aPL and use of GC [139] [140] [141]. Low-dose aspirin may be considered for primary prevention of CVD, as it may reduce the risk for incident CVD in SLE [142].
However, this must be viewed considering recent large studies in diabetics and elderly showing that the benefits of aspirin for primary CVD prevention are counterbalanced by the larger bleeding hazard [143] [144]. In addition to the human suffering attributed to the disease, there is the economic impact and the cost of disease management. These issues warrant research within the framework of the field of "Health Economics".